The complexity of intestinal permeability: Assigning the correct BCS classification through careful data interpretation

Moran Zur, Allison S. Hanson, Arik Dahan

Research output: Contribution to journalArticlepeer-review


While the solubility parameter is fairly straightforward when assigning BCS classification, the intestinal permeability (Peff) is more complex than generally recognized. In this paper we emphasize this complexity through the analysis of codeine, a commonly used antitussive/analgesic drug. Codeine was previously classified as a low-permeability compound, based on its lower Log P compared to metoprolol, a marker for the low-high permeability class boundary. In contrast, high fraction of dose absorbed (Fabs) was reported for codeine, which challenges the generally recognized Peff-F abs correlation. The purpose of this study was to clarify this ambiguity through elucidation of codeine's BCS solubility/permeability class membership. Codeine's BCS solubility class was determined, and its intestinal permeability throughout the small intestine was investigated, both in vitro and in vivo in rats. Codeine was found to be unequivocally a high-solubility compound. All in vitro studies indicated that codeine's permeability is higher than metoprolol's. In vivo studies in rats showed similar permeability for both drugs throughout the entire small-intestine. In conclusion, codeine was found to be a BCS Class I compound. No Peff-Fabs discrepancy is involved in its absorption; rather, it reflects the risk of assigning BCS classification based on merely limited physicochemical characteristics. A thorough investigation using multiple experimental methods is prudent before assigning a BCS classification, to avoid misjudgment in various settings, e.g., drug discovery, formulation design, drug development and regulation.

Original languageAmerican English
Pages (from-to)11-17
Number of pages7
JournalEuropean Journal of Pharmaceutical Sciences
Issue number1
StatePublished - 30 Sep 2014


  • BCS classification
  • Biowaiver
  • Drug solubility
  • Intestinal absorption
  • Segmental-dependent permeability

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science


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